Spermatogonial Differentiation Via Testicular Organoid

NCT06841861 | Recruiting Phase 1 FDA Drug

• 1 other identifier: SDTO 1
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose: This clinical trial aims to explore the potential for human sperm production in vitro by sustaining a laboratory-cultured adult testicular environment. It also seeks to identify genetic factors contributing to human sterility and failed spermatogenesis. The study's primary objectives include:

• Blood sample for serum analysis.
• A skin tissue biopsy.
• Testicular tissue, obtained through fine needle aspiration (FNA) or testicular sperm extraction (TESE), as part of a routine procedure. All procedures will be conducted by the principal investigator and qualified research staff, ensuring participant safety and adherence to ethical guidelines.

Conditions

Infertility, Male; Gene Abnormality; Sterility, Male

Outcome Measures

Primary Outcomes (1)

• Successful derivation of patient-specific human spermatogonial stem cells (hSSCs) from testicular tissue samples.

  Metric: The presence of viable hSSCs characterized by specific molecular and cellular markers (e.g., GFRα1, PLZF) within a predefined timeframe post-derivation. Assessment Method: Flow cytometry, immunohistochemistry, or RT-PCR to confirm marker expression.

  From initial sample collection to 24 months post all subject sample collection completion

Other Outcomes (3)

• Development and functional validation of an ex vivo testis organ-on-a-chip ('iTestis') platform for the cultivation and maintenance of isolated spermatogonial stem cells (hSSCs)

  From the date of the first successful derivation of patient-specific hSSCs until an ex vivo testis platform is developed and can functionally cultivate and maintain the isolated spermatogonial stem cells (hSSCs), assessed for up to 24 months.

• Promotion of human spermatogenesis in vitro ('iSperm') using hSSCs and hiPSCs within the iTestis platform.

  From the date of the initial development of the ex vivo testis platform until the promotion of human spermatogenesis using hSSCs and hiPSCs is achieved within the iTestis platform, assessed for up to 24 months.

• Successful derivation of patient-specific induced pluripotent stem cells (hiPSCs) from skin samples.

  From initial sample collection to 24 months post all subject sample collection completion.

Study Arms (4)

Fertile Males

ACTIVE COMPARATOR

Fertile male participants (control group) with no known infertility conditions undergoing a vasectomy reversal. Participants will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Genetic: Stem cell; Genetic: Genetic Screening; Genetic: Genetic Reprogramming; Genetic: Cell Maturation

Infertile Males with Genetic Sterility: Sertoli Cell Only

EXPERIMENTAL

Sterile male participants with unexplained or defined genetic infertility of sertoli cell only that are undergoing sperm mapping or testicular sperm retrieval (TESE) procedures. Participants will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Genetic: Stem cell; Genetic: Genetic Screening; Genetic: Genetic Reprogramming; Genetic: Cell Maturation

Infertile Males with Genetic Sterility: Early/Late Maturation Arrest

EXPERIMENTAL

Sterile male participants with unexplained or defined genetic infertility of early to late maturation arrest that are undergoing sperm mapping or testicular sperm retrieval (TESE) procedures. Participant will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Genetic: Stem cell; Genetic: Genetic Screening; Genetic: Genetic Reprogramming; Genetic: Cell Maturation

Infertile Men with Acquired Sterility

EXPERIMENTAL

Sterile male participants with acquired infertility from chemotherapy, infection, undecended testicles that are undergoing sperm mapping or testicular sperm retrieval (TESE) procedures. Participants will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Genetic: Stem cell; Genetic: Genetic Screening; Genetic: Genetic Reprogramming; Genetic: Cell Maturation

Interventions

Stem cell GENETIC

Primary cell cultures of tissue cells will be established. Cell cultures will undergo genetic reprogramming to induce the long-term propagation of living cells.

Fertile Males; Infertile Males with Genetic Sterility: Early/Late Maturation Arrest; Infertile Males with Genetic Sterility: Sertoli Cell Only; Infertile Men with Acquired Sterility

Genetic Screening GENETIC

Serum samples are processed through RNA sequencing to reveal known and novel infertility-related biomarkers and genes.

Also known as: genome mapping, genome characterization

Fertile Males; Infertile Males with Genetic Sterility: Early/Late Maturation Arrest; Infertile Males with Genetic Sterility: Sertoli Cell Only; Infertile Men with Acquired Sterility

Genetic Reprogramming GENETIC

Genes or gene products will be reinserted into cells to observe how the cells can be changed, or reprogrammed, into embryonic-like cells or into sperm precursor cells.

Fertile Males; Infertile Males with Genetic Sterility: Early/Late Maturation Arrest; Infertile Males with Genetic Sterility: Sertoli Cell Only; Infertile Men with Acquired Sterility

Cell Maturation GENETIC

Genetically unmodified and modified cells are placed in a laboratory-based testicular environment to promote spermatogenesis into maturity.

Fertile Males; Infertile Males with Genetic Sterility: Early/Late Maturation Arrest; Infertile Males with Genetic Sterility: Sertoli Cell Only; Infertile Men with Acquired Sterility

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male sex of reproductive age (between 18 - 60 years old).
• Evidence of fertility or normal spermatogenesis.
• Will undergo study procedures in conjunction with their planned fertility or infertility procedures performed for clinical purposes.
• Male sex of reproductive age (between 18 - 60 years old).
• Males with evidence of \>1 year of infertility.
• Posesses diagnosis of azoospermia is on clinical evaluation.
• Will undergo study procedures in conjunction with their planned fertility or infertility procedures performed for clinical purposes.

You may not qualify if:

• \- The lack of diagnosis of fertility or infertility, and lack of testicles.

Sponsors & Collaborators

• CellARTs Inc.: lead
• The Turek Clinic, Inc: collaborator

Study Sites (1)

The Turek Clinic

San Francisco, California, 94108, United States

RECRUITING

Related Publications (16)

• Ramathal C, Durruthy-Durruthy J, Sukhwani M, Arakaki JE, Turek PJ, Orwig KE, Reijo Pera RA. Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. Cell Rep. 2014 May 22;7(4):1284-97. doi: 10.1016/j.celrep.2014.03.067. Epub 2014 May 1.

  PMID: 24794432 BACKGROUND

• Kee K, Pera RA, Turek PJ. Testicular germline stem cells. Nat Rev Urol. 2010 Feb;7(2):94-100. doi: 10.1038/nrurol.2009.263. Epub 2010 Jan 19.

  PMID: 20084076 BACKGROUND

• Kossack N, Meneses J, Shefi S, Nguyen HN, Chavez S, Nicholas C, Gromoll J, Turek PJ, Reijo-Pera RA. Isolation and characterization of pluripotent human spermatogonial stem cell-derived cells. Stem Cells. 2009 Jan;27(1):138-49. doi: 10.1634/stemcells.2008-0439.

  PMID: 18927477 BACKGROUND

• Walsh TJ, Pera RR, Turek PJ. The genetics of male infertility. Semin Reprod Med. 2009 Mar;27(2):124-36. doi: 10.1055/s-0029-1202301. Epub 2009 Feb 26.

  PMID: 19247914 BACKGROUND

• Durruthy-Durruthy J, Briggs SF, Awe J, Ramathal CY, Karumbayaram S, Lee PC, Heidmann JD, Clark A, Karakikes I, Loh KM, Wu JC, Hoffman AR, Byrne J, Reijo Pera RA, Sebastiano V. Rapid and efficient conversion of integration-free human induced pluripotent stem cells to GMP-grade culture conditions. PLoS One. 2014 Apr 9;9(4):e94231. doi: 10.1371/journal.pone.0094231. eCollection 2014.

  PMID: 24718618 BACKGROUND

• Kogut I, McCarthy SM, Pavlova M, Astling DP, Chen X, Jakimenko A, Jones KL, Getahun A, Cambier JC, Pasmooij AMG, Jonkman MF, Roop DR, Bilousova G. High-efficiency RNA-based reprogramming of human primary fibroblasts. Nat Commun. 2018 Feb 21;9(1):745. doi: 10.1038/s41467-018-03190-3.

  PMID: 29467427 BACKGROUND

• Durruthy JD, Sebastiano V. Derivation of GMP-compliant integration-free hiPSCs using modified mRNAs. Methods Mol Biol. 2015;1283:31-42. doi: 10.1007/7651_2014_124.

  PMID: 25304205 BACKGROUND

• Huang P, Zhu J, Liu Y, Liu G, Zhang R, Li D, Pei D, Zhu P. Identification of New Transcription Factors that Can Promote Pluripotent Reprogramming. Stem Cell Rev Rep. 2021 Dec;17(6):2223-2234. doi: 10.1007/s12015-021-10220-z. Epub 2021 Aug 26.

  PMID: 34448118 BACKGROUND

• Gaur M, Ramathal C, Reijo Pera RA, Turek PJ, John CM. Isolation of human testicular cells and co-culture with embryonic stem cells. Reproduction. 2018 Feb;155(2):153-166. doi: 10.1530/REP-17-0346.

  PMID: 29326135 BACKGROUND

• Chui K, Trivedi A, Cheng CY, Cherbavaz DB, Dazin PF, Huynh AL, Mitchell JB, Rabinovich GA, Noble-Haeusslein LJ, John CM. Characterization and functionality of proliferative human Sertoli cells. Cell Transplant. 2011;20(5):619-35. doi: 10.3727/096368910X536563. Epub 2010 Nov 5.

  PMID: 21054948 BACKGROUND

• Bouyer C, Chen P, Guven S, Demirtas TT, Nieland TJ, Padilla F, Demirci U. A Bio-Acoustic Levitational (BAL) Assembly Method for Engineering of Multilayered, 3D Brain-Like Constructs, Using Human Embryonic Stem Cell Derived Neuro-Progenitors. Adv Mater. 2016 Jan 6;28(1):161-7. doi: 10.1002/adma.201503916. Epub 2015 Nov 10.

  PMID: 26554659 BACKGROUND

• Calamak S, Ermis M, Sun H, Islam S, Sikora M, Nguyen M, Hasirci V, Steinmetz LM, Demirci U. A Circulating Bioreactor Reprograms Cancer Cells Toward a More Mesenchymal Niche. Adv Biosyst. 2020 Feb;4(2):e1900139. doi: 10.1002/adbi.201900139. Epub 2020 Jan 14.

  PMID: 32293132 BACKGROUND

• Ishii T, Pera RA. Creating human germ cells for unmet reproductive needs. Nat Biotechnol. 2016 May 6;34(5):470-3. doi: 10.1038/nbt.3559. No abstract available.

  PMID: 27153270 BACKGROUND

• Ramathal C, Angulo B, Sukhwani M, Cui J, Durruthy-Durruthy J, Fang F, Schanes P, Turek PJ, Orwig KE, Reijo Pera R. DDX3Y gene rescue of a Y chromosome AZFa deletion restores germ cell formation and transcriptional programs. Sci Rep. 2015 Oct 12;5:15041. doi: 10.1038/srep15041.

  PMID: 26456624 BACKGROUND

• Durruthy Durruthy J, Ramathal C, Sukhwani M, Fang F, Cui J, Orwig KE, Reijo Pera RA. Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules. Hum Mol Genet. 2014 Jun 15;23(12):3071-84. doi: 10.1093/hmg/ddu012. Epub 2014 Jan 20.

  PMID: 24449759 BACKGROUND

• Medrano JV, Pera RA, Simon C. Germ cell differentiation from pluripotent cells. Semin Reprod Med. 2013 Jan;31(1):14-23. doi: 10.1055/s-0032-1331793. Epub 2013 Jan 17.

  PMID: 23329632 BACKGROUND

MeSH Terms

Conditions

Infertility, Male

Interventions

Genetic Testing; Chromosome Mapping

Condition Hierarchy (Ancestors)

Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Paul J Turek, MD

  Chief Medical Officer

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Erica S Godart, BS

CONTACT

4244579202; ericagodart@gmail.com

Constance John, PhD

CONTACT

4153054888; connie.john@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: All participants will be donating human tissue serum (blood), skin (via biopsy), and testicular tissue (via biopsy). These samples will be used for: 1. Primary cell culture of tissue cells will be established and genetic reprogramming could be applied to induce the long-term propagation of living cells. 2. Characterization and genetic screening of cells will be done to discover and reveal known or novel infertility-related biomarkers or genes. 3. Genetic reprogramming. Certain genes or gene products are inserted into donated cells to study how the cells can be changed, or reprogrammed, into embryonic-like cells or into sperm precursor cells. 4. Culture of cells in testicular organoids. Genetically unmodified or modified cells from donated samples could be placed in a laboratory-based testicular environment to see if sperm can be made.

Study Record Dates

• First Submitted: April 26, 2024
• First Posted: February 24, 2025
• Study Start: March 28, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): January 1, 2027
• Last Updated: February 24, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)